Anthracyclines rank among the most effective anti-cancer drugs ever developed. The first anthracyclines were isolated from Streptomyces peucetius early in the 1960s and were named doxorubicin (DOX) and daunorubicin (DNR). DOX and DNR both consist of an aglyconic and a sugar moiety. The aglycone consists of a tetracyclic ring with adjacent quinone-hydroquinone groups in rings C—B, a methoxy substituent at C-4 in ring D, and a short side chain at C-9 with a carbonyl at C-13. The sugar, called daunosamine, is attached by a glycosidic bond to the C-7 of ring A and consists of a 3-amino-2,3,6-trideoxy-L-fucosyl moiety. Daunorubicin has the structure:
The only difference between DOX and DNR is that the side chain at C-9 of DOX is a hydroxyacetyl, whereas that of DNR is acetyl. This difference is reflected in the spectrum of activity of DOX and DNR. Whereas DOX is an established component of treatment of breast cancer, childhood solid tumors, soft tissue sarcomas, and aggressive lymphomas, DNR shows activity in acute lymphoblastic or myeloblastic leukemias.
Unfortunately, the clinical use of both DOX and DNR is severely limited by the development of resistance in tumor cells and toxicity in healthy tissues. The toxicity to healthy tissues is manifested in cardiomyopathy and congestive heart failure (CHF). To avoid the latter, the maximum recommended cumulative doses of DNR and DOX have been generally recommended not to exceed 600 mg/m2. Chemists have spent decades identifying and/or synthesizing novel anthracyclines, looking for compounds superior to DOX or DNR in terms of activity and/or cardiac tolerability. The search has resulted in thousands of analogs, but only a handful have reached the stage of clinical development and approval, and the search for anthracyclins with improved specificity, activity and therapeutic ratio continues.